Cis 6-hydroxy-hexenoate

ABSTRACT

There is provided a novel method of preparing the highly desired odorant cis-3-hexen-1-ol from alkyl phenyl ethers. The method comprises Birch reduction of the alkyl phenyl ether, sequentially followed by oxidative ring cleavage and reduction.

nited States Patent [191 Dahill, J r.

[ Mar. 18, 1975 C18 6-HYDROXY-HEXENOATE [75] Inventor: Robert T. Dahill, Jr., Perth Amboy,

[73] Assignee: Givaudan Corporation, Clifton, NJ.

{22] Filed: June 15, I973 [211 App]. No.: 370,251

Related US. Application Data [62] Division of Ser. No. 49,544, June 24, I970, Pat. No.

OTHER PUBLICATIONS Agnes, G. et al., La Chimice e Llndustria (Milan) I968, 50(2), 194-196 (Ital).

Primary Examiner-Lorraine A. Weinberger Assistant E.\'aminer-Paul J. Killos Attorney, Agent, or Firm-Thomas Cifelli, Jr.

[57] ABSTRACT There is provided a novel method of preparing the highly desired odorant cis-3-hexen-I-ol from alkyl phenyl ethers. The method comprises Birch reduction of the alkyl phenyl ether, sequentially followed by oxidative ring cleavage and reduction.

3 Claims, N0 Drawings CIS 6-HYDROXY-HEXENOATE This is a division of application Ser. No. 49,544, filed June 24, 1970, now us. Pat. No. 3,836,513.

QSO -0-H C DESCRIPTION OF THE PRIOR ART Cis 3-hexen-Iol is a naturally occuring alcohol present in mulberry tree leaves, radish leaves, acaccia 2 leaves and other plants. I

It has been produced synthetically by an acetylenic routeby Bedoukian (Am. Perf. and Cos 78, 31 (1963). 10 Va This route, while practical is subject to the handling DESCRIPTION OF THE PREFERRED problems known to affect industrial scale acetylenic EMBODIMENT route synthesis.

The alkyl phenyl ethers of formula (I) are well known SUMMARY OF THE INVENTION in the art I h process fth present reaction on alkyl phenyl In the Birch reduction there is prepared a solution of ether (I) is subjected to l,4-ring reduction suitably by the compound I to be reduced, suitably in dry ether and the action of an alkali metal solvated in an amine tothe ethereal solution added to liquid ammonia. Alkali gcther with a proton source, for example, by means of metal, suitably sodium, potassium or lithium is added the Birch reduction. The l,2-double bond is cleaved by thereto. The mixture is allowed to stand, suitably with selective oxidation, suitably by ozonolysis to yield the agitation until all of the metal has dissolved. An alka aldehyde ester (III) which is not isolated but is reduced nol, suitably ethanol is added until the blue color disapto the alcohol (IV) esterification of the alcohol (IV) pears and the ammonia permitted to evaporate atambiwith a sulfonyl halide followed by further reduction ent temperature. Water is trdded and the reaction yields the desired alcohol (VI). worked up in the usual manner.

The reaction sequence is illustrated as follows: In place of using ammonia as the solvent. an alkyl on I I wherein R is lower alkyl of 1-6 carbons or lower cyclo- 5 amine may be used. Ether may be used. It is preferred alkyl of 48 carbons. however to operate in liquid ammonia due to the rela- And Q is alkyl, of l-6 carbons, aryl for example phetive ease of obtaining a solution of alkali metals. "Yb tolyli 0r p y Where the alkyl g p has In yet another modification the Birch reduction may bons and the y group for example P y or P be performed electrolytically by passing direct current Y through a solution of the aromatic ether, lithium chlo- Alternativelyv Where R is P y the reaction p ride and methyl amine. While this method is not the Cedes m an analogous mannermethod of choice in small scale synthesis. the elimina- OR tion of the cooling and condensation facilities required 0 for liquid-ammonia may make it the method of choice for industrial synthesis. i In the liquid ammonia modification there are utilized from about 10 to about 20 volumes of liquid ammonia to each part by weight of aryl ether. There is employed ma) 2 an excess of alkali metal. suitably 4.5 moles of metalfl Ira mole of aryl ether.

In the electrolytic method one can use 8 moles of lithium chloride and 30 moles of mthyl amine per 0 mole of aryl ether.

C 5 A current density of 0.2 amps/cm at volts.

The temperature is maintained at the boiling point of the amine.

2 The enol ether (i.e., 1,2-) is then oxidatively cleaved,

cleavage may be accomplished by epoxidation, conver- IV sion to glycol and oxidation with periodic acid, permanganate oxidation, or ozonlysis; preferred among these methods however is ozonolysis.

In this modification the diene (II) is taken up in a suitable solvent, preferably an alkanol such as methanol and cooled to dry ice temperature (ca-78C).

An equimolar amount of ozone is then introduced in the usual manner at this temperature. The excess ozone is then flushed out with an inert gas and the mixture permitted to warm up to about C.

The ozonide isthen decomposed and subsequently, (in situ) reduced to the corresponding alcohol ester (IV). Among the suitable reducing agents may be mentioned dimethyl sulfide, sodium iodide, potassium iodide, zinc or magnesium in the presence of acetic acid or water, sulfur dioxide or sources thereof such as sodium bisulfite, stannous chloride, formaldehyde and inorganic or organic phosphites or similar mild reducing agents known to the art.

Raney nickel may also be employed, as may catalytic hydrogenation. This last is not favored due to the control required to ensure that reduction does not proceed too far.

Of these reducing agents dimethyl sulfide is preferred. There is added a slight excess of this reagent, from 1 to 2 moles of sulfide per mol of ozonide, suitably about 1.5 moles of sulfide per mole being preferred.

Without further work-up the reaction mixture containing the aldehyde ester (III) is reduced to the corresponding alcohol. In the preferred method there is added a slight excess of sodium borohydride in an alkanol, suitably in absolute ethanol. These are utilized between 1 and 2, suitably about 1.5 moles of sodium borohydride per mole of originally charged alkyl cyclohexadienyl ether (II).

The addition is carried out at dry ice temperatures (ca-78C). After addition of the reducing agent the reaction mixture is allowed to warm to ambient temperatures and stirred for from about one to about 2 hours.

The solventsare then removed, suitably by distillation under reduced pressure to yield the hydroxy ester (IV), which may be further purified by distillation.

The hydroxy ester (IV) is then reduced to the desired hexenylalcohol (VI). In this step the hydroxy group of ester (IV) is sulfonated, suitably by reaction with a sulfonyl halide suitably an alkyl, aryl, or alkaryl sulfonyl halide, such as toluene sulfonyl chloride, methane sulfonyl chloride and the like in the usual manner by mixing the reactants at moderately low temperatures, say about 0C in a weak organic base such as triethylamine or pyridine, followed by acidification and extraction of the product by a water immiscible solvent.

The ester sulfonate (V) is then reduced to the desired hexenol (VI). Among the preferred reducing agents are: lithium aluminum hydride and lithium in liq. Nl-l Especially preferred is lithium aluminum hydride. The ester sulfonate (V) is taken up in a suitable solvent, such as benzene, tetrahydrofuran or diethyl ether to which is added an excess of lithium aluminum hydride in a similar solvent. There are utilized from about 1 to about 2 moles of reducing agent per mole of sulfonate Work-up in the usual manner yields the desired alcohol (VI).

grance compositions (see M. Barnard, Parfumerie.

Cosmetique, Savons 5, 105 (1962)).

EXAMPLE I l-Methoxyl, 4-cyclohexadiene A solution of] 50 g. of anisole in 500 ml. ofdry ether and 2 liters ofliquid ammonia which was distilled from sodium was placed in a 5 1. three necked flask fitted with a mechanical agitator, dry ice condenser and dropping funnel and cooled with a dry ice-ethyl alcohol bath. To this mixture was added 45 g. of lithium wire in small pieces. After the addition was complete, absolute ethyl alcohol (about 1250 ml.) was added until the blue color disappeared. The resulting mixture was left in a good exhaust hood for the ammonia to evaporate. Water (500 ml.) was cautiously added to the resulting mixture and the precipitate filtered off. The organic layer was separated and the water layer extracted three times with 100 ml. of ether. The combined organic solutions were washed neutral with water and dried over anhydrous potassium carbonate. The solvent was removed by atmospheric distillation through a 37 cm. column packed with glass helices. There was produced 132.4 g. (86.5% of theory). This material analyzed as 92.5% l-methoxy-l, 4-cyclohexadiene and 7.5%

l-methoxy-1,3-cyclohexadiene. B. p. -80C (11 I.R.: 5.90 2, 6.05p.(olefin), 8 20[.L(I101 ether) N.M.R.:

4.301(2H, multiplet, olefinic protons), 5.351'( 1H, broad, olefinic protons), 6.48'1-(3H, singlet, -OCQ), 7.257(4H, multiplet, CH

EXAMPLE I] Methylcis 6-hydroxy-3-hexenoate A mixture of 2.85 g. (26 mmoles) of l-methoxy-l. 4-cyclohexadiene and 30 ml. of absolute methanol was treated with ozone (1.25 g., 26 mmoles) at 78C. The resulting mixture was flushed with nitrogen. The mixture was allowed to come to 0C and 2.42 g. (39 mmoles) of dimethylsulfide were added and the mixture stirred at this temperature for 80 minutes. After cooling to 78C, a suspension of 1.47 g/ (39 mmoles) EXAMPLE III Methyl cis 6-hydroxy-3 hexenoate p-toluene sulfonate p-Toluene sulfonyl chloride (1.425 g.. 7.5 mm.) was added at 0C to a solution of g. (6.95 mm.) of methyl cis 6-hydroxy-3-hexenoate in 2.37 g. of dry pyridine. The resulting mixture was stirred at 0C for 4 hours. The crude product was poured on ice and concentrated hydrochloric acid, extracted with benzene,

N.M.R.:

2.657(4l-l, multiplet, aromatic), 4.407(2H, multiplet, olefinic), 5.937(2H, triplet, .l=7, -C lh-O), 6.317(3H, singlet, OCH 6.947(2H, doublet, J=8, -Cl -C-), 7.567(3H, singlet, CH3) 7.627(2H, multiplet, --CH -CH=) EXAMPLE IV Cis 3-hexen-l-ol Crude methyl cis 6-hydroxy-3-hexenoate p-toluene sulfonate (1.357 g., 4.85 mm.) was dissolved in 20 ml. of dry ether. To this solution was added 0.342 g. (9.00 mm.) of lithium aluminum hydride in 20 ml. of dry ether at 25 with stirring. After the addition was completed the mixture was stirred at 25for 1 hour. The excess lithium aluminum hydride was decomposed by the addition of first wet ether and finally water. The produce was extracted with ether and dried over sodium sulfate. After the ether was evaporated the product was distilled through a short path distillation apparatus to give 0.358 g. (3.58 mm., 74% of theory) of Cis 3- hexen-l-ol, b.p. 70 (27 mm.).

l.R.: 3.00 (--OH), 1380 2 EXAMPLE V l-Ethoxy-l, 4-cyclohexadiene A solution of 59.5 g. of phenetole (ethyl phenyl ether) in 200 ml. of dry ether and 800 ml. ofliquid ammonia which was distilled from sodium was placed in a 2 l. three necked flask fitted with a mechanical agitator, dry ice condenser and dropping funnel and cooled with a dry ice ethyl alcohol bath. To this mixture was added 14.1 g. of lithium wire in small pieces. After the addition was complete, absolute ethyl alcohol (about 400 ml.) was added until the blue color disappeared.

The resulting mixture was left in a good exhaust hood for the ammonia to evaporate. Water (200 ml.) was cautiously added to the resulting mixture and the precipitate filtered off. The organic layer was separated and the water layer extracted three times with 50 ml. of ether. The combined organic solutions were washed neutral with water and dried over anhydrous potassium carbonate. The solvent was removed by atmospheric distillation through a 37 cm. column packed with glass helices. There was produced 45 g. (75% of theory). This material analyzed as 86% l-ethoxy-l ,3- cyclohexadiene.

I.R.: 5.90,u, 6.05u(olefinic). 8.30,u.(enol ether) N.M.R.:

4.357 (2H, multiplet, olefinic protons) 5.407 (1H, broad, olefinic proton) 6.357 (2H, quartet, 1 7, OCfl2) 7.277 (4H, multiplet, -CH2-) 8.757 (3H, triplet, .l=7, -Cfl3) EXAMPLE V1 Ethyl cis 6-hydroxy-3-hexenoate A mixture of 6.30 g. (50 mmoles) of l-ethoxy-l. 4- cyclohexadiene and 100 m1. of absolute methanol was treated with ozone (2.40 g., 50 mmoles) at 78C. The resulting mixture was flushed with nitrogen. The mixture was allowed to come to 0C. and 4.84 g. (78 mmoles) of dimethylsulfide were added and the mixture stirred at this temperature for 80 minutes. The alcohol was removed under vacuum to produce 5.1 g. (32.3 mmole, of theory) of ethyl cis 6 hydroxy-3 hexenoate, b.p. (0.3 mm., short path distillation).

4.42 7 (2H, multiplet, olefinic) 5.92 7 (2H, quartet, 1 8, OCfl -CH 6.37 7 (2H, J=7, triplet, CH OH) 6.95 7 (2H, J=6, doublet, Cl -l C=Ol 7.70 7 (3H, multiplet. Cfl and -Oll) 8.75 7 (3H, triplet, 1 8, OCH- Cl -l EXAMPLE V11 Ethyl cis 6-hydroxy-3-hexenoate ptoluene sullonate p-Toluene sulfonyl chloride (1.425 g. 7.5mm.) was added at 0C to a solution of 1.00 g. (6.3mm) of ethyl cis 6-hydroxy-3,hexenoate in 10 g. of dry pyridine. The resulting mixture was stirred at 0C for 4 hours. The crude porduct was poured on ice and concentrated hydrochloric acid, extracted with benzene, washed with 2N hydrochloric acid, sodium carbonate till neutral and dried over potassium carbonate. Evaporation of the solvent produced 1.42 g. (4.85 mm., 77% of theory) of product homogeneous at 225C. on a 20 M vpc column.

I.R.: 5.80,u.(C=O); 6.25uand 6.98M C=C 2.657(4H, multiplet aromatic) 4.407(2H, multiplet, olefinic) 5.967(4H, multiplet, -Cfl -O) 6.947(2H, doublet, J=8,

7.557(3H, singlet, -CH3) 7.657(2H, miltiplet, QH -CH=) 8.667(3H, triplet. 1 8. gi -CH EXAMPLE V111 cis 3-Hexen-1-ol Crude ethyl cis 6-hydroxy-3-hexenoate p-toluene sulfonate (l.43 g., 4.85 mm.) was dissolved in 20 ml. of dry ether. To this solution was added 342 mg. (9.00

EXAMPLE IX l-lsopropoxy-l ,4-cyclohexadiene A solution of 65 g. of isopropyl phenyl ether in 250 ml. of dry ether and one liter of liquid ammonia which was distilled from sodium was placed in a 3 liter necked flask fitted with a mechanical agitator, dry ice condenser and dropping funnel and cooled with a dry iceethyl alcohol bath. To this mixture was added l6.6 g. of lithium in small pieces. After the addition was complete, absolute ethyl alcohol (about 460 ml.) was added until the blue color disappeared. The resulting mixture was left in a good exhaust hood for the ammonia to evaporate. Water (200 ml.) was cautiously added to the resulting mixture and the precipitate filtered off. The organic layer separated and the water layer extracted three times with 100 ml. of ether. The combined organic solutions were washed neutral with water and dried over anhydrous potassium carbonate. The solvent was removed by atmospheric distillation through a 37 cm. column packed with glass helices. There was produced 44.5 g. (68% of theory) of lisopropoxy-l,4-cyclohexadiene b.p. 6l5 (8 mm.).

I.R.: 5.95,u. 6.10 (olefin), 8.l2,u(enol ether). N.M.R.:

4.301 (2H, multiplet, olefinic protons) 5.351 (1H, broad, olefinic proton) 5.751 lH, heptet, Cfl (CH J 6) 7.281 (4H, multiplet, -CH- 8.801 (6H, doublet, CH (Cfl h, J 6) EXAM PLE X lsopropyl cis-6-hydroxy-3-hexenoate A mixture of 3.60 g. (26 mm.) of l-isopropoxy-l,4- cyclohexadiene and 100 ml. of absolute methanol was treated with ozone (1.25 g., 26 mm.) at 78C. The resulting mixture was flushed with nitrogen. The mixture was allowed to come to C. and 2.42 g. (39 mm.) of dimethyl sulfide were added and the mixture stirred at this temperature for 80 minutes. After cooling to 78C. a suspension of 1.47 g. (39 mm.) of sodium borohydride in ml. of absolute ethanol was added dropwise. The resultingmixture was allowed to come up to room temperature and then stirred for 80 minutes. The methanol was removed under vacuum to product 3.54 g. of product (80% of theory), b.p. 72 (0.2 mm., short path distillation) 4.381(2H, multiplet, oletinic) 5.021(1H, heptet, J=6,

6.371(2H, triplet, J=6, -ci o 6.931(2H, doublet, j=7, --CH2-CO-) 8 7.681(3H, multiplet, Ofi -CH 8.801(6H, doublet,

EXAMPLE Xl lsopropyl cis 6-hydroxy-3-hexenoate p-toluene sulfonate p-Toluene sulfonyl chloride (1.425 g., 7.5 mm.) was added at 0C to a solution of 1.00 g. (5.8 mm.) of isopropyl cis 6-hydroxy-3-hexenoate in 2.37 g. ofdry pyridine. The resulting mixture was stirred at 0C for 4 hours. The crude product was poured on ice and concentrated hydrochloric acid, sodium carbonate till neutral and dried over potassium carbonate. Evaporation of the solvent produced 1.32 g. of theory) of crude tosylate.

I.R.: 5.80/L(C=O), 6.26 and6.98u( C=C) N.M.R.:

2.771(4H, multiplet, aromatic) 4.481(2H. multiplet, olefinic) 5.041(1H, heptet, .l=6,

o-cg

6.00'r(2H, triplet, J=7, CI -I O 7.051(2H, doublet, J=8,

7.601(3H, singlet, Cfi 7.671(2H, multiplet, -Cl;l CH'=) 8.821(6H, doublet. J=7,

EXAMPLE Xll cis 3-Hexen-l-ol Thecrude isopropyl cis 6-hydroxy-3-hexenoate ptoluene sulfonate (1.00 g.. 3.07 mmoles) was dissolved in 20 ml. of dry ether. To this solution was added 342 mg. (9.00 mm.) of lithium aluminum hydride in dry ether. After the addition was-complete the mixture was stirred at 25C for 1 hour. The excess lithium aluminum hydride was decomposed with first wet ether and finally water. The product was extracted with ether. dried over magnesium sulfate and the solvent evaporated. There was produced 0.26 g. (2.6 mm.. 84.5% of theory) VPC was identical with authentic sample.

EXAMPLE XllI In accordance with the procedures of Examples l-ll. but starting in place of anisole. with n-propoxy benzene. n-butoxy benzene. tert.butoxy benzene. npentoxy benzene. cyclopentoxy benzene, cyclohexoxy benzene, cycloheptoxy benzene or diphenyl ether, there is obtained n-propyl cis-6-hydroxy-3-hexenoate n-butyl cis-6-hydroxy-3-hexenoate tert.butyl cis-6-hydroxy-3-hexenoate n-pentyl cis-6-hydroxy3-hexenoate cyclopentyl-cis-6-hydroxy-3-hexenoate cyclohexyl cis-6-hydroxy-3- hexenoate cycloheptyl cis-6-hydroxy-3-henenoate and cis-6-hydroxy-3-hexenoyl anhydride EXAMPLE XIV In accordance with the procedures of Examples Ill, but where in place of methyl cis-6-hydroxy-3- hexenoate there are utilized the products of Example XIII there are obtained the corresponding p-toluene sulfonates.

EXAMPLE XV In accordance wtih the procedures of Examples Ill, VII, and XIV but where in place of p-toluene sulfoyl chloride, there is utilized benzene sulfonyl chloride or methyl sulfonyl chloride, there are obtained the corresponding benzene sulfonates and methane sulfonates respectively.

JASMIN FLOWER (PERFUME COMPOSITION) -Continued JASMIN FLOWER (PERFUME COMPOSITION) a'Amyl cinnamaldehyde 2 l0 Dimethyl Benzyl carbinyl acetate 5 p-Cresol (pure) 5 Ncrol 30 Benzyl 55 Absolute civette 107: I0

Example XVII Cognac Type Flavor (Flavor Composition) Furfurul 1% 5O Bcnzaldehyde l7( 50 Cyclotene ['71 30 Palotone 1% l0 Mcth 'lhen 'I- lvcidate eth 'l este r l /r y g' 3 2O Paraldehyde I07: 30 Caproic acid 10% I0 Tincture of vanillin 10%) 30 Balsam of Tolu 1071 10 Isobutyl acetate 30 Cis 3-hexenol 10% 2O Enanthic ether 40 Ethyl palargonate 3t) Banana (Haarman and Reimer) 40 Ethyl Acetoacetate 50 Amyl Laurate l0 Ethyl lactate 1 l0 Ethyl butyrate 0 Essence of the sediment of the wine of Alsace 30 Pyroligneous alcohol simple 300 Alcohol 969? What is claimed is: l. A cis 6-hydroxy3-hexenoate of the formula wherein R is lower alkyl of l6 carbons or cyclo alkyl of 4-8 carbon atoms.

2. A compound according to claim 1 wherein R is selected from the group consisting of methyl. ethyl and isopropyl.

3. A compound according to claim 2 wherein R is methyl.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTICN a Patent No. 5,872,160 Dated March 18-, 1975 Inventor s Robert T. Dahill, Jr.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below: G

Column 1, line A2, last structural formula "VII" should read VI Column line 62, "CH should read CH 6 Column 5, line 16, "CH5" should read CH Column 5, lines 20-50, "produce" should read product Column 7, line i, "either" should read ether Column 7, line 5 "product" should read produce Column 8, line 25, "C=o" should read C=O a Column 8, line 52, "CH -O" should read CH -O) Signed and Sealed this Twentieth Day of July 1976 Q [SEAL] Attest:

RUTH c. MASON c. MARSHALL DANN Arresting Officer Commissioner ofPatents and Trademarks 

1. A CIS 6-HYDROXY-3-HEXENOATE OF THE FORMULA
 2. A compound according to claim 1 wherein R is selected from the group consisting of methyl, ethyl and isopropyl.
 3. A compound according to claim 2 wherein R is methyl. 